Gas-filled microbubbles with an encapsulating shell, generally referred to as ultrasound contrast agents (UCAs), are used regularly in diagnostic ultrasound, and are becoming important in therapeutic ultrasound applications. However, there is a need to better understand the physical interaction of ultrasound with UCAs, to enable UCAs to be more effectively used in diagnostic and therapeutic applications. Toward this goal, researchers have used acoustic scattering, attenuation, noise emission, and optical microscopy to study ultrasound/bubble interaction in connection with UCAs.
A basic characterization of UCAs typically involves measurement of their attenuation (scattering and absorption). These measurements provide information about the resonance frequency of the bubbles, and their damping. Some information about bubble populations can also be inferred from the measurements. However, there does not appear to be any correlation between attenuation and UCA performance or functionality. Broadband noise has also been used to obtain information about UCAs and their effect on the environment. Studies have found that a cavitation dose (a measure of initial cavitation activity) correlates very well with hemolysis (the destruction of red blood cells and associated release of hemoglobin) in vitro, suggesting that hemolysis can potentially be used as a measure of cavitational activity. Researchers have also compared the inertial cavitation thresholds of various UCAs by examining noise spectra, although thresholds obtained in this way are only indicative of relatively violent collapses, but not of less violent microbubble fragmentation mechanisms. Other research has shown how cavitational activity depends on pulse parameters in vivo, suggesting that optimal imaging is obtained when cavitation is reduced. As with attenuation measurements, noise emissions do not necessarily correlate with UCA performance or functionality.
A more direct approach to characterizing UCA performance involves determining acoustical backscattering, especially since diagnostic ultrasound is based on detecting backscattered signals. A variety of detection modalities have been used, including sub-harmonic, second-harmonic, and super-harmonic detection. In addition, various pulse schemes have increased the signal-to-noise ratio (SNR) of the acoustical data collection system. Such modalities, however, are limited because of a fundamental lack of understanding of the physics of ultrasound/microbubble interaction. For example, backscattering signatures are often machine dependent, or concentration dependent, but these dependencies are not well understood.
Recently, fundamental information about the interaction of ultrasound with UCAs has been obtained by using high-speed cameras. In these studies, single UCAs were insonified with pulses from a single element transducer, and the results were imaged with a camera, providing direct information about the response of the UCAs to the ultrasound. Although the image quality provided by high-speed cameras is excellent, and important information about bubble response and bubble destruction can be obtained in this manner, high-speed cameras are expensive, and the amount of data obtained are small. Usually only one, or at most, a few acoustic cycles of data can be collected, often requiring the splicing together of data from multiple experiments to achieve results that can yield the information being sought.
It would thus be desirable to provide approaches for investigating the physical properties of UCAs, particularly with respect to the properties of UCAs in the presence of ultrasound. The apparatus required to perform such investigations should be of modest expense.